tbuckley/cabot-search huggingface dataset:
Deciphering possible mechanisms of action in pathophysiology of osteosarcoma: PI3K-Akt/MAPK pathways contribute to tumorigenesis versus FoxO/mTOR/HIF-1 pathways involved in metastasis.
Authors: Changye Zou, Zhiqiang Zhao, Mingxian Xu, Weitang Guo, Jintao Huang, Xin Zhang, Dong You, Jingnan Shen
Journal: Journal of Clinical Oncology (2022)

e23515 Background: Osteosarcoma is a kind of primary bone malignancies with high invasiveness and poor prognosis. However, effective therapy for osteosarcoma is still lacking. In fact, the advancement of clinical practice and innovative therapy was hindered by the limited understanding of the genetic characteristics and the mechanism of metastasis. Exploration of the mutational and evolutionary features of osteosarcoma is warranted. Methods: A total of 24 samples of matched primary and metastatic lesions were collected from 12 osteosarcoma patients. Targeted sequencing including 672 cancer-related genes was conducted in 9 patients while whole exome sequencing was performed in 3 patients. Results: High-frequency mutation genes were TP53 (42%), FLCN (33%), GID4 (33%), ATRX (25%), CCND3 (25%) in primary osteosarcoma, comparing to FLCN (42%), GID4 (42%), CCNE1 (25%), MYO15A (25%), ATRX (25%) in metastatic lesion. The PI3K-Akt and MAPK signaling pathway was significantly enriched in both primary (PI3K, p &lt; 0.001; MAPK, p &lt; 0.001) and metastatic lesions. (PI3K, p &lt; 0.001; MAPK, p &lt; 0.001), Additionally, chromosome region 17p11.2, including the driver genes NCOR1, MAP2K4, ALOX12B, AURKB, CDK12, was significantly amplified in primary (G-score = 1.9, q-value = 0.06) and metastatic lesions (G-score = 3.2, q-value &lt; 0.001). These data suggested that changes of PI3K and MAPK pathways and amplification of region 17p11.2 may contribute to initial osteosarcoma tumorigenesis and possibly early metastasis. In contrast, the FoxO, mTOR and HIF-1 signaling pathway were only enriched in metastatic lesions (FOXO, p &lt; 0.001; mTOR, p &lt; 0.05; HIF-1, p &lt; 0.001), implying that these pathways may be critical for osteosarcoma metastatic occurrence. Finally, clonality analysis showed that cellular clonal prevalence (CCF) of subclones including diver genes of ATRX, MYO15A and MYB, were increased ( ATRX: P, CCF = 0.59, M, CCF = 0.74; MYO15A: P, CCF = 0.43, M, CCF = 0.52; MYB: P, CCF = 0.11, M, CCF = 0.52) in metastatic lesions, which further confirmed that alterations of ATRX and MYO15A were considerably vital for osteosarcoma. Conclusions: The abnormal changes of PI3K-Akt and MAPK signaling pathway as well as the amplification of 17p11.2 chromosome region may contribute to osteosarcoma tumorigenesis and possibly early metastasis; whereas pathways of FoxO, mTOR, HIF-1 and driver genes including ATRX, MYO15A and MYB, may play a key role in the metastasis of osteosarcoma.
Repeat prostate biopsies for Atypical Small Acinar Proliferation in the era of Multiparametric Magnetic Resonance Imaging
Authors: B.L. Teixeira, A. Marques-Pinto, J.F. Cabral, G.G. Mendes, J.R. Correia, C.M. Tavares, M. Madanelo, M.A. Rocha, S. Mesquita, I. Palma, M.M. Monteiro, A. Fraga
Journal: European Urology (2022)
Drugging the undruggable-targeting P53: A comparative analysis of APR-246 and coti-2 in human tumor primary culture explants.
Authors: Adam Jeremiah Nagourney, Steven Scott Evans, Max Serge Duesberg, Paulo D'Amora, Paula J. Bernard, Eric Francisco, Robert Alan Nagourney
Journal: Journal of Clinical Oncology (2022)

e15092 Background: The TP53 tumor suppressor is the most commonly mutated gene in human cancer. P53 protein comprised of 393 amino acids functions as a tetramer with the loss of function mutations concentrated in “hotspots” that often affect DNA binding domains. APR-246 and COTI-2 are novel small molecules that are under clinical investigation for the treatment of P53 mutated cancers. APR, a quinuclidine binds to P53 cysteine residues altering the functional conformation while COTI is a thio-semicarbazone, found active in P53 mutant tumors using a novel computational platform. As the mechanisms of action may differ we undertook a comparative analysis of these compounds in 3D human tumor explants derived from surgical specimens. Methods: Ex Vivo Analyses of Programmed Cell Death (EVA/PCD) (D’Amora, P et al Gyn. Oncol. 2021) was applied to 236 human tumor primary culture explants isolated from surgical specimens. After disaggregation, micro-spheroids, isolated by precise density centrifugation were exposed to APR, COTI and other agents for 72-96 hours. Drug-induced cell death was measured by delayed-loss-of-membrane integrity and ATP content (luciferase). Dose response curves were interpolated to LC50 values. Synergy analysis used the method of Chou &amp; Talalay. Correlation coefficients used Pearson moment. Results: APR and COTI reveal the highest activity in hematologic neoplasms. Solid tumor activity patterns diverged with COTI active in gynecologic malignancies and NSCLC and moderately active in breast and colorectal while APR is active in colorectal but less active in breast and NSCLC. Pearson moments for COTI vs APR revealed an R value = 0.146 (NS). COTI activity correlated with Nitrogen Mustard and Alpelisib (PIK3CA) while APR activity correlated with Doxorubicin and Everolimus. COTI combinations focused upon ovarian cancers identified synergy in 25% and antagonism in 18%. Conclusions: P53’s function as the “guardian of the genome” is consistent with our findings that many cytotoxic and targeted agents that induce cell death reveal correlations with APR and COTI. While APR affects the structural conformation of P53, COTI may function downstream via oxidative, metabolic or other stress responses. The correlation coefficient for APR vs COTI at 0.146 (NS) suggests distinct mechanisms of action. This is supported by different disease-specific-profiles and correlations with other drugs. COTI synergy in ovarian cancers, the target of current clinical trials at 25% is below expectations. With differing disease specificities, selecting between these and related agents to optimize clinical outcomes may require a more granular examination of cellular mechanisms of response and resistance. Primary culture analyses offer insights into drug mechanisms of action, combinatorial potential and have the capacity to improve patient selection.
GALLANT: A phase 2 study using metronomic gemcitabine, doxorubicin, nivolumab, and docetaxel as second/third-line therapy for advanced sarcoma (NCT04535713).
Authors: Noufil Adnan, Simranjit Sekhon, Sant P. Chawla, Ted T. Kim, Victoria S. Chua-Alcala, Mitchel Fernando, Amir Ahari, William Feske, Doris V. Quon, Erlinda Maria Gordon
Journal: Journal of Clinical Oncology (2022)

11518 Background: In our experience, combinatorial therapy with lower doses of doxorubicin, gemcitabine, and docetaxel has been effective with a manageable toxicity profile in patients with advanced soft tissue sarcomas. Hypothesis: The addition of nivolumab will have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival; Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, &gt; 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if toxicity grade is &lt;1. Results: This is an Interim Report on the modified Intent-to-treat population (n = 43). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. The most common histological subtypes in this group include leiomyosarcoma (n = 15), pleomorphic sarcoma (n = 4), synovial sarcoma (n = 4), liposarcoma (n = 3), osteosarcoma (n = 3) and other (n = 10). Best Overall Response = 2 CR (surgical CR), 6 PR, 30 SD, 5 PD. The disease control rate (CR+PR+SD) was 88.4%. Median PFS was &gt; 4.6 (range: 1-27) months; 4 month PFS rate 60%. Median OS 6.2 months, with 4-month OS 74%. Historically, the median PFS on preceding lines of therapy was 2 (range: 1-14) months. There were no unexpected side effects noted in this study. The most common grade 3/4 TRAEs include Fatigue (n = 13), Nausea (n = 9), Neutropenia (n = 8), thrombocytopenia (n = 6), Anemia (n = 6). Conclusions: The GALLANT protocol using metronomic Gemcitabine, Doxorubicin (Adriamycin), Nivolumab, and Docetaxel (Taxotere) (1) is an effective regimen as second/third-line therapy for advanced sarcoma with no unexpected side effects, and (2) may have synergistic activity when this metronomic chemotherapy is combined with an immune checkpoint inhibitor. Clinical trial information: NCT04535713.
Neoadjuvant Toripalimab plus chemotherapy in patients with stage IIB-IIIB NSCLC: A single-center, prospective, single-arm, phase 2 trial (Renaissance Study).
Authors: Shi Yan, Jinfeng Chen, Jia Wang, Chao Lv, Jiwang Bi, Xin Yang, Shaolei Li, Yuzhao Wang, Xiang Li, Yue Yang, Nan Wu
Journal: Journal of Clinical Oncology (2022)

e21128 Background: Neoadjuvant treatment of a programmed cell death protein 1 (PD-1) inhibitor plus chemotherapy has been shown to be promising in treating resectable non-small cell lung cancer (NSCLC). The current study aimed to investigate the efficacy and safety of toripalimab plus double platinum-based chemotherapy as neoadjuvant treatment for stage IIB-IIIB NSCLC. Methods: Study eligibility involved stage IIB-IIIB, wildtype EGFR/ALK NSCLC pts with ECOG PS 0-1 status. Pts received 2-4 cycles of toripalimab (240mg, q3w) plus cisplatin-based chemotherapy. All pts were assessed by imaging/surgical indication after the second cycle of treatment. Pts who cannot undergo surgery will be reassessed after another 1-2 cycles of neoadjuvant therapy. Primary endpoints were major pathological response (MPR), complete pathological response (pCR). Secondary endpoints were objective response rate (ORR), R0 resection rate and safety. Results: A total of 52 eligible pts (median age: 62, IQR: 45-76; female: 4, 7.7%) were enrolled and received 2-4 cycles neoadjuvant treatment since Mar 2021. 42 pts had squamous cell carcinoma and 10 pts had non-squamous cell carcinoma. Disease distribution in stage IIB, IIIA and IIIB consisted of 14, 30 and 8 pts, respectively. 15 pts were undergoing preoperative treatment or preparing for surgery, 32 pts underwent resection (median interval between neoadjuvant treatment and surgery: 67 days, IQR 39-113), 5 pts were unsuitable for surgery (1 pt had immune-related pneumonia; 2 pts who had stable disease were considered radical radiotherapy and immunotherapy for maintenance due to the difficulty of surgery induced by tumor location and lymph node metastasis; 2 pts continued toripalimab plus chemotherapy or radiotherapy due to high surgical risk induced by old age and poor performance status). 20 pts (20/32, 62.5%) achieved MPR, including 16 pts (16/32, 50%) with pCR. 6 pts (6/8, 75%), 12 pts (12/18, 66.7%), and 2 pts (2/6, 33.3%) with stage IIB, IIIA and IIIB achieved MPR respectively. R0 resection was achieved for all 32 pts (100%). 23 pts underwent surgery with cN2/N1 at baseline (23/24, 95.8%) achieved nodal downstaging. For pts who finished radiological reassessment (45 pts finished the treatment schedule and only 43 pts finished radiological reassessment), ORR was 83.7% (36/43). Grade 1-2 TRAEs were reported in 33 patients (33/45, 73.3%). Grade 3-4 TRAEs were reported in 6 pts (6/45, 13.3%). Conclusions: Toripalimab plus platinum-based doublet as neoadjuvant treatment yields a high MPR rate, manageable toxicity and feasible surgical resection in stage IIB-IIIB NSCLC. Clinical trial information: NCT04606303.
Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least first-line therapy: Interim results of a single-arm phase II trial.
Authors: Huaying Wang, Wenjuan Tian, Yulan Ren, Chuyu Jing, Boer Shan
Journal: Journal of Clinical Oncology (2022)

5591 Background: For advanced or recurrent endometrial cancer (EC), therapeutic options remain scarce. Immune or antiangiogenic monotherapy has shown moderate efficacy in EC. Preclinical and clinical data showed that camrelizumab (an anti-PD-1 antibody) plus apatinib (a selective VEGFR2 inhibitor) markedly enhanced anti-tumor efficacy in multiple solid tumors. This study was designed to assess the efficacy and safety of the combination of camrelizumab and apatinib as second-line or above therapy for advanced or recurrent EC. Methods: This was an open-label, single-arm, phase II trial conducted in China. Patients with advanced or recurrent EC who progressed after at least first-line therapy received camrelizumab (200 mg, intravenously, q2w) plus apatinib (250 mg, orally, qd). Using a minimax Simon two-stage design, 21 patients were enrolled at stage I and if a complete or partial response was observed in at least four patients, the enrollment would be continued to 40 patients. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included time to objective response (TTR), disease control rate (DCR), duration of Response (DoR), progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF) and safety. Here, the results of stage I are reported. Results: Between January 20, 2020 and July 8, 2021, 21 patients were enrolled. The median age was 57 years (range 29–72). Thirteen patients (61.9%) had ECOG PS of 0, and eight patients (38.1%) received at least two prior therapies. As of November 9, 2021, the median follow-up time was 13.5 months (IQR 11.3-16.3). Among 21 evaluable patients, the confirmed ORR was 47.6% (95% CI 25.7%-70.2%) with complete response in one patient (4.8%) and partial response in nine patients (42.9%); eight patients had stable disease for a DCR of 85.7% (95% CI 63.7%-97.0%). The median PFS was 11.8 months (95% CI 5.2-14.4). Treatment-related adverse events (TRAEs) of any grade and of grade ≥ 3 were reported in 21 (100%) patients and 10 (47.6%) patients, respectively. The most common grade ≥ 3 TRAEs included gamma-glutamyltransferase increased (six [28.6%]), direct bilirubin increased (four [19.0%]), alanine aminotransferase increased (three [14.3%]), aspartate aminotransferase increased (three [14.3%]) and hyperglycaemia (three [14.3%]). Four patients (19.0%) experienced reactive cutaneous capillary endothelial proliferation, all of which were grade 1-2. No treatment-related deaths were reported. Conclusions: Camrelizumab plus apatinib demonstrated promising antitumor activity and a manageable safety profile in patients with advanced or recurrent EC after failure of at least first-line therapy. Clinical trial information: ChiCTR2000031932.
Predictors for metastatic renal cell carcinoma in IMDC favorable risk group treated with a single agent first line systemic therapy.
Authors: Ryuichi Mizuno, Nobuyuki Tanaka, Kazuhiro Matsumoto, Mototsugu Oya
Journal: Journal of Clinical Oncology (2022)

e16518 Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors, the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of a single agent systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 240 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 patients were classified as favorable risk group based on the IMDC Risk Category and received a single agent systemic therapy. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46 months after first-line treatment initiation, the median progression free survival (PFS) for first line treatment and OS of patients in favorable risk group were 29 months (95% CI 21–34)) and not reached, respectively. The estimated percentage of patients who were alive at 12 and 24 months were 96 and 94%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.97, 95% confidence interval [CI]: 0.94–0.99, p = 0.0299) and the metastases limited to lung (HR: 3.85, 95% CI: 1.08–24.50, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusions: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.
Preanalytical protocols for improving access to live tissue diagnostics in remote and low resource settings.
Authors: Areesha A. Charania, Heli K. Patel, Zeenia Punjani, Zeelu H. Patel, Georgios Papachristou, Carlo M. Contreras, Allan Tsung, Karim I. Budhwani
Journal: Journal of Clinical Oncology (2022)

e13501 Background: Nearly 70% of diagnostics lab test errors occur due to variability in preanalytical factors. Preanalytical factors comprise parameters from the time tissue is extracted from the patient to the time it is tested in the lab. For lack of standardized preanalytical protocols, integrity of collected specimens is often compromised. This is particularly pronounced when specimens are collected in remote or low resource settings and shipped to testing facilities. Establishing preanalytical protocols could serve as an important resource for remote collection sites and substantially reduce variability in the integrity of specimens thereby improving lab test rigor and reproducibility and promote innovation in live tissue diagnostic tests for personalized medicine. Objective: The aim of this study is to analyze impact of cold chain logistics on integrity of collected solid tumor tissue specimens. Specifically, duration in transit, container and wet ice packing, and composition of transport media were assessed. Methods: Baseline protocols for biospecimen preanalytical parameters were established from literature review. Standard aseptic lab protocols were implemented for all experiments including preparation of transport media, tissue transport kits, transport kit packaging, tumor tissue transfer in tissue transport kits, tissue receiving, and tissue integrity assessment. Transport was simulated for human and murine pancreatic ductal adenocarcinoma (PDAC) tissue by holding packaged tumor tissue containers in storage for the duration of transport. Saline solution, basal media, and complete media were evaluated as transport media. Specimen integrity was evaluated using live/dead assays in high-content imaging systems at 24- and 48-hour intervals. Results: For human and murine tumor tissue, viability was optimal when tissue was transported in Nalgene jars containing complete media packaged in ¼” thick wall Styrofoam containers tightly packed in wet ice for transport. While specimens fared well over both 24- and 48- hour simulated shipping durations, temperature and humidity logs from sensors embedded in the packages showed sharp degradation in packaging environment with longer durations of time. Conclusions: Establishing preanalytical protocols would improve rigor and reproducibility in diagnostic lab tests by improving tissue viability and integrity. Such protocols would also enable next generation cancer models to further enhance predictive capacity in translational research and subsequently in personalized medicine applications at the bedside.
EPEN-29. Spatial transcriptomic analysis of ependymoma implicates unresolved wound healing as a driver of tumor progression
Authors: Andrew Donson, Rui Fu, gregory Norris, Nicholas Willard, Andrea Griesinger, Kent Riemondy, Vladimir Amani, Enrique Grimaldo, Faith Harris, Todd Hankinson, Siddhartha Mitra, timothy Ritzmann, Richard Grundy, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract Ependymoma is a childhood brain tumor that remains incurable in approximately 50 percent of cases, most commonly in posterior fossa subgroup A (PFA). Uncovering how heterogeneous cell types within the tumor microenvironment (TME) interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA TME have been revealed by single-cell RNAseq (scRNAseq), identifying divergent epithelial differentiation and epithelial-mesenchymal transition (EMT) lineages. Here, we utilize spatial transcriptomics (Visium) of 14 PFA samples, integrated with scRNAseq, to chart neoplastic and immune cell architecture, with a higher resolution of cellular heterogeneity than scRNAseq alone. At a gross level, all PFA were primarily comprised of neoplastic epithelial and mesenchymal transcriptomic spatial zones, each containing a diversity of hierarchical cellular stages. In all samples we revealed spatially and transcriptomically-distinct mesenchymal zone-associated subclusters, including a quiescent undifferentiated progenitor-like subpopulation and clusters with characteristics of early and late stage EMT. Two early stage EMT clusters were distinguished by signatures of either myeloid cell interaction or hypoxia, and both were demonstrated to be EMT-initiating processes in in-vitro PFA experimental models. Myeloid cell interaction is the predominant initiating stage of EMT in PFA, occurring in zones that are spatially distinct from hypoxia induced EMT. Other mesenchymal clusters represent later EMT stages characterized by wound repair and tissue remodeling. Increased proliferation was a general characteristic of epithelial zone clusters, which included a second undifferentiated progenitor-like population that showed a particularly high mitotic rate and was associated with histologically hypercellular areas. Given the biological parallels with normal wound healing, we propose that mesenchymal and epithelial zones interact to create a cycle of persistent tissue damage response and mitogenic re-epithelialization signals. Unresolved wound repair is therefore a potential driver of PFA progression, a new concept that could provide novel targets for effective therapeutic intervention.